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International Review of Cell and... 2016Phosphatidylethanolamine (PE) is the second most abundant glycerophospholipid in eukaryotic cells. The existence of four only partially redundant biochemical pathways... (Review)
Review
Phosphatidylethanolamine (PE) is the second most abundant glycerophospholipid in eukaryotic cells. The existence of four only partially redundant biochemical pathways that produce PE, highlights the importance of this essential phospholipid. The CDP-ethanolamine and phosphatidylserine decarboxylase pathways occur in different subcellular compartments and are the main sources of PE in cells. Mammalian development fails upon ablation of either pathway. Once made, PE has diverse cellular functions that include serving as a precursor for phosphatidylcholine and a substrate for important posttranslational modifications, influencing membrane topology, and promoting cell and organelle membrane fusion, oxidative phosphorylation, mitochondrial biogenesis, and autophagy. The importance of PE metabolism in mammalian health has recently emerged following its association with Alzheimer's disease, Parkinson's disease, nonalcoholic liver disease, and the virulence of certain pathogenic organisms.
Topics: Alzheimer Disease; Animals; Autophagy; Candida; Carboxy-Lyases; Cell Membrane; Cytidine Diphosphate; Ethanolamines; Humans; Lipid Metabolism; Methylation; Mitochondria; Non-alcoholic Fatty Liver Disease; Oxidative Phosphorylation; Parkinson Disease; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids; Prions; Protein Processing, Post-Translational; Virulence
PubMed: 26811286
DOI: 10.1016/bs.ircmb.2015.10.001 -
International Journal of Molecular... May 2021All nations which have undergone a nutrition transition have experienced increased frequency and falling latency of chronic degenerative diseases, which are largely... (Review)
Review
All nations which have undergone a nutrition transition have experienced increased frequency and falling latency of chronic degenerative diseases, which are largely driven by chronic inflammatory stress. Dietary supplementation is a valid strategy to reduce the risk and severity of such disorders. Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator with extensively documented anti-inflammatory, analgesic, antimicrobial, immunomodulatory and neuroprotective effects. It is well tolerated and devoid of side effects in animals and humans. PEA's actions on multiple molecular targets while modulating multiple inflammatory mediators provide therapeutic benefits in many applications, including immunity, brain health, allergy, pain modulation, joint health, sleep and recovery. PEA's poor oral bioavailability, a major obstacle in early research, has been overcome by advanced delivery systems now licensed as food supplements. This review summarizes the functionality of PEA, supporting its use as an important dietary supplement for lifestyle management.
Topics: Amides; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Dietary Supplements; Endocannabinoids; Ethanolamines; Humans; Inflammation; Inflammation Mediators; Neuroprotective Agents; Pain; Palmitic Acids
PubMed: 34069940
DOI: 10.3390/ijms22105305 -
Gut Oct 2023Ample evidence exists for the role of abnormal gut microbiota composition and increased gut permeability ('leaky gut') in chronic inflammation that commonly co-occurs in...
OBJECTIVE
Ample evidence exists for the role of abnormal gut microbiota composition and increased gut permeability ('leaky gut') in chronic inflammation that commonly co-occurs in the gut in both obesity and diabetes, yet the detailed mechanisms involved in this process have remained elusive.
DESIGN
In this study, we substantiate the causal role of the gut microbiota by use of faecal conditioned media along with faecal microbiota transplantation. Using untargeted and comprehensive approaches, we discovered the mechanism by which the obese microbiota instigates gut permeability, inflammation and abnormalities in glucose metabolism.
RESULTS
We demonstrated that the reduced capacity of the microbiota from both obese mice and humans to metabolise ethanolamine results in ethanolamine accumulation in the gut, accounting for induction of intestinal permeability. Elevated ethanolamine increased the expression of microRNA- by enhancing ARID3a binding on the miR promoter. Increased decreased the stability of zona occludens-1 () mRNA, which in turn, weakened intestinal barriers and induced gut permeability, inflammation and abnormalities in glucose metabolism. Importantly, restoring ethanolamine-metabolising activity in gut microbiota using a novel probiotic therapy reduced elevated gut permeability, inflammation and abnormalities in glucose metabolism by correcting the ARID3a// axis.
CONCLUSION
Overall, we discovered that the reduced capacity of obese microbiota to metabolise ethanolamine instigates gut permeability, inflammation and glucose metabolic dysfunctions, and restoring ethanolamine-metabolising capacity by a novel probiotic therapy reverses these abnormalities.
TRIAL REGISTRATION NUMBER
NCT02869659 and NCT03269032.
Topics: Mice; Animals; Humans; Gastrointestinal Microbiome; Mice, Obese; Diabetes Mellitus, Experimental; Inflammation; Obesity; Glucose; Permeability; MicroRNAs; Ethanolamines
PubMed: 36948576
DOI: 10.1136/gutjnl-2022-327365 -
International Journal of Molecular... Oct 2020Palmitoylethanolamide (PEA, -hexadecanoylethanolamide) is an endogenous compound belonging to the family of -acylethanolamines. PEA has anti-inflammatory and analgesic... (Review)
Review
Palmitoylethanolamide (PEA, -hexadecanoylethanolamide) is an endogenous compound belonging to the family of -acylethanolamines. PEA has anti-inflammatory and analgesic properties and is very well tolerated in humans. In the present article, the basal pharmacology of PEA is reviewed. In terms of its pharmacokinetic properties, most work has been undertaken upon designing formulations for its absorption and upon characterising the enzymes involved in its metabolism, but little is known about its bioavailability, tissue distribution, and excretion pathways. PEA exerts most of its biological effects in the body secondary to the activation of peroxisome proliferator-activated receptor-α (PPAR-α), but PPAR-α-independent pathways involving other receptors (Transient Receptor Potential Vanilloid 1 (TRPV1), GPR55) have also been identified. Given the potential clinical utility of PEA, not least for the treatment of pain where there is a clear need for new well-tolerated drugs, we conclude that the gaps in our knowledge, in particular those relating to the pharmacokinetic properties of the compound, need to be filled.
Topics: Amides; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Ethanolamines; Gene Expression Regulation; Humans; PPAR alpha; Palmitic Acids; Receptors, Cannabinoid; Tissue Distribution
PubMed: 33114698
DOI: 10.3390/ijms21217942 -
Pain Physician Jul 2017Palmitoylethanolamide (PEA) is a cannabimimetic compound that has been investigated as an analgesic agent in animal models and clinical trials. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Palmitoylethanolamide (PEA) is a cannabimimetic compound that has been investigated as an analgesic agent in animal models and clinical trials.
OBJECTIVES
We conducted a meta-analysis to examine the efficacy of PEA for treating pain in randomized, controlled trials.
STUDY DESIGN
Systematic review and meta-analysis.
SETTING
This meta-analysis examined all randomized, controlled trials involving the effect of PEA on pain score.
METHODS
We searched PubMed and Embase for randomized, active or placebo-controlled trials of PEA for the treatment of acute or chronic pain. Our primary outcome was the weighted mean difference in visual analog pain scales of PEA treatment compared to inactive controls.
RESULTS
We identified 10 studies including data from 786 patients who received PEA and 512 controls for inclusion in our systematic review. Eight trials included an inactive control group and were included in the meta-analysis. PEA was associated with significantly greater pain reduction compared to inactive control conditions (WMD = 2.03, 95% CI: 1.19 - 2.87, z = 4.75, P < 0.001). Use of placebo control, presence of blinding, allowance for concomitant treatments, and duration or dose of PEA treatment did not affect the measured efficacy of PEA. All-cause dropout was non-significantly reduced in the PEA group compared to inactive control conditions (RR = 0.36, 95% CI: 0.10 - 1.26, z = -1.60, P = 0.11).
LIMITATIONS
This meta-analysis relied on a relatively small number of trials across a variety of conditions causing pain with differing trial designs. Overall quality of the underlying studies and assessment of side effects were often poor.
CONCLUSIONS
PEA may be a useful treatment for pain and is generally well tolerated in research populations. Further, well-designed, randomized, placebo-controlled trials are needed to provide reliable estimates of its efficacy and to identify less serious adverse events associated with this compound.
KEY WORDS
PEA, palmidrol, palmitoylethanolamide, efficacy, pain, pain management, meta-analysis.
Topics: Acute Pain; Amides; Analgesics; Chronic Pain; Ethanolamines; Humans; Outcome Assessment, Health Care; Palmitic Acids
PubMed: 28727699
DOI: No ID Found -
The Journal of Allergy and Clinical... Mar 2023The Global Initiative for Asthma recommends that low-dose inhaled corticosteroid (ICS)/formoterol be preferred to short-acting beta-agonists as reliever therapy in... (Review)
Review
The Global Initiative for Asthma recommends that low-dose inhaled corticosteroid (ICS)/formoterol be preferred to short-acting beta-agonists as reliever therapy in adolescents and adults with asthma, across the range of asthma severity. This recommendation represents the most fundamental change in asthma management for many decades. In this commentary, we review the rationale for combination ICS/formoterol therapy, the evidence on which this recommendation has been made, the limitations in the evidence, the practical issues relevant to the implementation of ICS/formoterol reliever-based regimens in clinical practice, and the emerging evidence for the efficacy and safety of combination ICS/salbutamol reliever therapy regimens.
Topics: Adult; Adolescent; Humans; Formoterol Fumarate; Budesonide; Bronchodilator Agents; Anti-Asthmatic Agents; Asthma; Adrenal Cortex Hormones; Drug Therapy, Combination; Administration, Inhalation; Ethanolamines
PubMed: 36639054
DOI: 10.1016/j.jaip.2023.01.002 -
Cardiovascular Drugs and Therapy Oct 2022Bisoprolol and nebivolol are highly selective β-adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with... (Review)
Review
Therapeutic Properties of Highly Selective β-blockers With or Without Additional Vasodilator Properties: Focus on Bisoprolol and Nebivolol in Patients With Cardiovascular Disease.
Bisoprolol and nebivolol are highly selective β-adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with reduced left ventricular ejection fraction (HFrEF), ischaemic heart disease (IHD), and hypertension. Nebivolol has additional vasodilator actions, related to enhanced release of NO in the vascular wall. In principle, this additional mechanism compared with bisoprolol might lead to more potent vasodilatation, which in turn might influence the effectiveness of nebivolol in the management of HFrEF, IHD and hypertension. In this article, we review the therapeutic properties of bisoprolol and nebivolol, as representatives of "second generation" and "third generation" β-blockers, respectively. Although head-to-head trials are largely lacking, there is no clear indication from published studies of an additional effect of nebivolol on clinical outcomes in patients with HFrEF or the magnitude of reductions of BP in patients with hypertension.
Topics: Adrenergic beta-Antagonists; Benzopyrans; Bisoprolol; Cardiovascular Diseases; Ethanolamines; Heart Failure; Humans; Hypertension; Myocardial Ischemia; Nebivolol; Stroke Volume; Vasodilator Agents; Ventricular Function, Left
PubMed: 34106365
DOI: 10.1007/s10557-021-07205-y -
Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma.Cancer Research Jan 2023The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore,...
UNLABELLED
The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the NAD+/NADH and pyruvate/lactate ratios and also the α-ketoglutarate/2-hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and β-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and β-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma.
SIGNIFICANCE
Targeting cancer metabolism using the mitochondrial uncoupler niclosamide ethanolamine leads to methylome reprogramming and differentiation in neuroblastoma, providing a therapeutic opportunity to reverse the Warburg effect and suppress tumor growth. See related commentary by Byrne and Bell, p.167.
Topics: Animals; Mice; beta Catenin; Cell Differentiation; Cell Line, Tumor; Epigenome; Ethanolamine; Ethanolamines; Hypoxia; Neuroblastoma; Niclosamide; Warburg Effect, Oncologic; Mitochondria
PubMed: 36318118
DOI: 10.1158/0008-5472.CAN-22-1029 -
Advances in Therapy May 2022Inhaled corticosteroid (ICS)-containing therapies are the mainstay of pharmacological management of asthma. They can be administered alone or in combination with a... (Review)
Review
Inhaled corticosteroid (ICS)-containing therapies are the mainstay of pharmacological management of asthma. They can be administered alone or in combination with a long-acting bronchodilator, depending on asthma severity, and may also be supplemented with short-acting bronchodilators for as-needed rescue medication. Adherence to asthma therapies is generally poor and characterized by underuse of ICS therapies and over-reliance on short-acting bronchodilators, which leads to poor clinical outcomes. This article reviews efficacy versus systemic activity profiles for various dosing regimens of budesonide (BUD) and fluticasone propionate (FP). We performed a structured literature review of BUD and FP regular daily dosing, and BUD/formoterol (FOR) as-needed dosing, to explore the relationship between various dosing patterns of ICS regimens and the risk-benefit profile in terms of the extent of bronchoprotection and cortisol suppression. In addition, we explored how adherence could potentially affect the risk-benefit profile, in patients with mild, moderate, and moderate-to-severe asthma. With a specific focus on BUD or FP-containing treatments, we found that regular daily ICS and ICS/long-acting β-agonist (LABA) dosing had a greater degree of bronchoprotection than as-needed BUD/FOR dosing or BUD/FOR maintenance and reliever therapy (MART) dosing, and still maintained low systemic activity. We also found that the benefits of regular daily ICS dosing regimens were diminished when adherence was low (50%); the shorter duration of bronchoprotection observed was similar to that seen with typical as-needed BUD/FOR usage. These findings have implications for aiding clinicians with selecting the most suitable treatment option for asthma management, and subsequent implications for the advice clinicians give their patients.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Budesonide; Budesonide, Formoterol Fumarate Drug Combination; Drug Combinations; Ethanolamines; Fluticasone; Formoterol Fumarate; Humans
PubMed: 35284999
DOI: 10.1007/s12325-022-02092-7 -
BMJ Open Respiratory Research Dec 2021Uncontrolled asthma is associated with substantial morbidity. While fast-acting bronchodilators provide quick relief from asthma symptoms, their use as rescue fails to... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of as-needed albuterol/budesonide versus albuterol in adults and children aged ≥4 years with moderate-to-severe asthma: rationale and design of the randomised, double-blind, active-controlled MANDALA study.
INTRODUCTION
Uncontrolled asthma is associated with substantial morbidity. While fast-acting bronchodilators provide quick relief from asthma symptoms, their use as rescue fails to address the underlying inflammation. Combining a short-acting beta-agonist, such as albuterol (salbutamol), with an inhaled corticosteroid, such as budesonide, in a single inhaler as rescue therapy could help control both bronchoconstriction and inflammation, and reduce the risk of asthma exacerbations.
METHODS AND ANALYSIS
The Phase 3 MANDALA study was designed to determine the efficacy of albuterol in combination with budesonide (albuterol/budesonide 180/160 µg or 180/80 µg, two actuations of 90/80 µg or 90/40 µg, respectively) versus albuterol (180 µg, two actuations of 90 µg) as rescue therapy in adult, adolescent and paediatric patients with moderate-to-severe asthma. This event-driven study enrolled symptomatic patients (3000 adults/adolescents and 100 children aged 4-11 years) who experienced ≥1 severe asthma exacerbation in the previous year and were receiving maintenance therapy for ≥3 months prior to study entry. The primary efficacy endpoint was time-to-first severe asthma exacerbation.
ETHICS AND DISSEMINATION
The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice and the applicable regulatory requirements.
TRIAL REGISTRATION
NCT03769090.
Topics: Administration, Inhalation; Adolescent; Adult; Albuterol; Asthma; Budesonide; Child; Drug Combinations; Ethanolamines; Formoterol Fumarate; Humans
PubMed: 34887317
DOI: 10.1136/bmjresp-2021-001077